ETS-1 Protein Regulates Vascular Endothelial Growth Factor-induced Matrix Metalloproteinase-9 and Matrix Metalloproteinase-13 Expression in Human Ovarian Carcinoma Cell Line SKOV-3

Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, 4 Raja S. C. Mullick Road, Kolkata 700032, India.
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2012; 287(18):15001-15. DOI: 10.1074/jbc.M111.284034
Source: PubMed


Matrix metalloproteinase-mediated degradation of extracellular matrix is a crucial event for invasion and metastasis of malignant
cells. The expressions of matrix metalloproteinases (MMPs) are regulated by different cytokines and growth factors. VEGF, a potent angiogenic cytokine, induces invasion of ovarian
cancer cells through activation of MMPs. Here, we demonstrate that invasion and scattering in SKOV-3 cells were induced by
VEGF through the activation of p38 MAPK and PI3K/AKT pathways. VEGF induced the expression of MMP-2, MMP-9, and MMP-13 and hence regulated the metastasis of SKOV-3 ovarian cancer cells, and the activities of these MMPs were reduced after inhibition
of PI3K/AKT and p38 MAPK pathways. Interestingly, VEGF induced expression of ETS-1 factor, an important trans-regulator of
different MMP genes. ETS-1 bound to both MMP-9 and MMP-13 promoters. Furthermore, VEGF acted through its receptor to perform the said functions. In addition, VEGF-induced MMP-9 and MMP-13 expression and in vitro cell invasion were significantly reduced after knockdown of ETS-1 gene. Again, VEGF-induced MMP-9 and MMP-13 promoter activities were down-regulated in ETS-1 siRNA-transfected cells. VEGF enriched ETS-1 in the nuclear fraction in a dose-dependent manner. VEGF-induced expression
of ETS-1 and its nuclear localization were blocked by specific inhibitors of the PI3K and p38 MAPK pathways. Therefore, based
on these observations, it is hypothesized that the activation of PI3K/AKT and p38 MAPK by VEGF results in ETS-1 gene expression, which activates MMP-9 and MMP-13, leading to the invasion and scattering of SKOV-3 cells. The study provides a mechanistic insight into the prometastatic
functions of VEGF-induced expression of relevant MMPs.

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Available from: Moitri Basu, Jan 26, 2016
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    • "found that SAS cells stimulated with P. gingivalis exhibited sustained activation of Ets1 and phosphorylation of HSP27, while proMMP9 production was inhibited by knockdown of Ets1 or HSP27. Our findings are consistent with several previous reports, as proMMP9 expression was shown to be regulated by ERK1/2-Ets1 and p38/ HSP27 in a number of cell lines (Hansen et al., 2001; Liu et al., 2005; Ghosh et al., 2012), and knockdown of ERK1/2 and Ets1 decreased proMMP9 mRNA expression in response to TGFβ1 (Liu et al., 2005). Moreover, cancer cell migration and invasion were reported to be inhibited by knockdown of Ets1 and HSP27 (Hahne et al., 2005; Shin et al., 2005), and p38 deficiency inhibited HSP27 and MMP9 expression (Kumar et al., 2010). "
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    ABSTRACT: Recent epidemiological studies have revealed a significant association between periodontitis and oral squamous cell carcinoma (OSCC). Furthermore, matrix metalloproteinase 9 (MMP9) is implicated in the invasion and metastasis of tumor cells. We examined the involvement of Porphyromonas gingivalis, a periodontal pathogen, in OSCC invasion through induced expression of proMMP and its activation. proMMP9 was continuously secreted from carcinoma SAS cells, while P. gingivalis infection increased proenzyme expression and subsequently processed it to active MMP9 in culture supernatant, which enhanced cellular invasion. In contrast, Fusobacterium nucleatum, another periodontal organism, failed to demonstrate such activities. The effects of P. gingivalis were observed with highly invasive cells, but not with the low invasive type. P. gingivalis also stimulated proteinase-activated receptor 2 (PAR2) and enhanced proMMP9 expression, which promoted cellular invasion. P. gingivalis mutants deficient in gingipain proteases failed to activate MMP9. Infected SAS cells exhibited activation of ERK1/2, p38, and NF-kB, and their inhibitors diminished both proMMP9-overexpression and cellular invasion. Together, our results show that P. gingivalis activates the ERK1/2-Ets1, p38/HSP27, and PAR2/NFκB pathways to induce proMMP9 expression, after which the proenzyme is activated by gingipains to promote cellular invasion of OSCC cell lines. These findings suggest a novel mechanism of progression and metastasis of OSCC associated with periodontitis.
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    • "Ets-1 upregulation appears to associate specifically with more advanced, invasive tumors in breast and ovarian carcinomas [17-22], and is positively correlated with the enhanced metastatic potential of numerous cancers [17,23-26]. Indeed, there are many well-established target genes for Ets-1 that are closely linked to cancer progression, particularly mediators of extracellular matrix degradation, cancer cell migration and angiogenesis [16,25,27-31]. Thus, the consequences of Ets-1 overexpression are particularly relevant to the study of ovarian cancer as this type of malignancy is very difficult to detect, and is most commonly diagnosed at advanced stages of disease progression that include metastases. "
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    • "It is quite possible that βhCG/hCG induces the generation of a single molecule which in turn leads to the generation of the others via autocrine loops. Indeed, while both IL-8 and VEGF induce the production of MMP-2 and MMP-9 [48], [49], IL8 up-regulates VEGF [50] and VEGF has been shown to enhance IL-8 levels [51]. Whether such a scenario is at work here is under investigation. "
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